US20050085497A1 - HMG-CoA reductase inhibitors and method - Google Patents

HMG-CoA reductase inhibitors and method Download PDF

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US20050085497A1
US20050085497A1 US10/946,055 US94605504A US2005085497A1 US 20050085497 A1 US20050085497 A1 US 20050085497A1 US 94605504 A US94605504 A US 94605504A US 2005085497 A1 US2005085497 A1 US 2005085497A1
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Saleem Ahmad
Jeffrey Robl
Khehyong Ngu
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Bristol Myers Squibb Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/622—Forming processes; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/626—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B
    • C04B35/63—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B using additives specially adapted for forming the products, e.g.. binder binders
    • C04B35/632—Organic additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to compounds and pharmaceutical compositions useful as hypocholesterolemic and hypolipidemic agents. More particularly, this invention concerns (1) certain inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) that include a pyridine- or a pyrimidine-containing nucleus attached by means of a linker to an HMG-binding domain sidechain, (2) pharmaceutical compositions containing such compounds and (3) a method of lowering blood serum cholesterol levels and modulating blood serum lipid levels employing such pharmaceutical compositions.
  • HMG-CoA reductase 3-hydroxy-3-methylglutaryl-coenzyme A reductase
  • Rosuvastatin is also disclosed in Masamichi Watanabe et al. (Bioorganic & Medicinal Chemistry (1997), 5(2), 437-444).
  • Japanese Patent Application 06256318-A (corresponding to Japanese Patent 3197971 granted Aug. 1, 2001) discloses 5-carboalkoxy pyrimidine derivatives of the structure where R 1 , R 2 and R 3 can be independently H, alkyl, aryl or heteroaryl, and A can be NR 7 R 8 where R 7 and R 8 can be independently H, alkyl, aryl and heteroaryl among others. It is disclosed that these compounds are intermediates for preparing HMG CoA reductase inhibitors.
  • EP367895 discloses pyrimidinyl-substituted hydroxyacids, lactones and esters which are inhibitors of cholesterol biosynthesis and have the structure where R 1 can be alkyl;
  • pyridine- and pyrimidine-containing compounds that are potent inhibitors of cholesterol biosynthesis by virtue of their ability to inhibit the enzyme 3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase).
  • the present invention provides compounds of the formula I wherein X is N or CR 5 ;
  • the Z group will be in form of a free acid, a physiologically acceptable and hydrolyzable ester or 8 lactone thereof, or an alkali metal salt, alkaline earth metal salt, an amine salt or an amino acid salt.
  • R 1 is aryl (especially substituted aryl as defined hereinafter);
  • Most preferred compounds of formula I of the invention will have the structure or an alkali or alkaline earth metal (such as Na, K or Ca) salt thereof, or an amino acid salt (such as arginine), or an amine salt thereof, wherein R 8 and R 9 are the same or different and independently selected from H, halogen and/or alkyl (preferably 4-fluoro, 4-fluoro-3-methyl or 3,5-dimethyl); and
  • the present invention provides pharmaceutical compositions, useful as hypolipidemic or hypocholesterolemic agents, or hypotriglyceridemic agents, or anti-Alzheimer's agents, or anti-osteoporosis agents as well as other uses as described herein, which contain a hypolipidemic or hypocholesterolemic or hypotriglyceridemic or anti-Alzheimer's disease or anti-osteoporosis amount, or other therapeutically effective amount (depending upon use) of a compound of formula I in accordance with this invention, in combination with a pharmaceutically acceptable carrier.
  • the present invention provides a method of inhibiting cholesterol biosynthesis or lowering blood serum cholesterol levels and/or modulating blood serum cholesterol levels such as lowering LDL cholesterol and/or increasing HDL cholesterol, and/or lowering triglycerides, or treating dyslipidemia, mixed dyslipidemia, hyperlipidemia, hypercholesterolemia, hypo ⁇ -lipoproteinemia, LDL Pattern B, LDL Pattern A, hyperlipoproteinemia or hypertriglyceridemia, and other aberrations of apolipoprotein B metabolism, or reducing levels of Lp(a), or treating or preventing other cholesterol-related diseases, or treating or preventing or reversing progression of atherosclerosis, or preventing or treating Alzheimer's disease, or preventing or treating osteoporosis and/or osteopenia, or reducing inflammatory markers such as C-reactive protein, or preventing or treating low grade vascular inflammation, or preventing or treating stroke, or preventing or treating dementia, or preventing and treating coronary heart disease (including primary and secondary prevention of myocardial infarction, or
  • a method for preventing or treating diabetes, especially Type 2 diabetes, and related diseases such as insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, Syndrome X, diabetic complications, dysmetabolic syndrome, and related diseases, and sexual dysfunction, wherein a therapeutically effective amount of a compound of structure I or composition containing same is administered to a patient in need of treatment.
  • diabetes especially Type 2 diabetes, and related diseases such as insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, Syndrome X, diabetic complications, dysmetabolic syndrome, and related diseases, and sexual dysfunction
  • a method for preventing and treating malignant lesions (such as ductal carcinoma in situ of the breast and lobular carcinoma in situ of the breast), premalignant lesions (such as fibroadenoma of the breast and prostatic intraepithelial neoplasia (PIN), gastrointestinal malignencies, liposarcomas and various other epithelial tumors (including breast, prostate, colon, ovarian, gastric and lung), cancer-induced asthenia (fatigue), irritable bowel syndrome, Crohn's disease, gastric ulceritis, and gallstones, and HIV infection, other infectious diseases, drug-induced lipodystrophy, and proliferative diseases such as psoriasis, wherein a therapeutically effective amount of a compound of structure I or a composition containing same is administered to a human patient in need of treatment.
  • malignant lesions such as ductal carcinoma in situ of the breast and lobular carcinoma in situ of the breast
  • premalignant lesions such as fibroadenoma of
  • a method for improving coagulation homeostasis including reducing plasminogen activating inhibitor (PAI)-1 activity, reducing fibrinogen, and/or reducing platelet aggregation, and/or improving endothelial function, wherein a therapeutically effective amount of a compound of structure I or a composition containing same is administered to a patient in need of treatment.
  • PAI reducing plasminogen activating inhibitor
  • a method for treating cholesterol related diseases, diabetes and related diseases, cardiovascular diseases, cerebrovascular diseases as defined above and hereinafter and other diseases as set out above, wherein a therapeutically effective amount of a combination of a compound of structure I and a hypolipidemic agent, and/or lipid modulating agent and/or antidiabetic agent and/or cardiovascular agent, cerebrovascular agent, and/or other type of therapeutic agent, is administered to a patient in need of treatment.
  • the compound of structure I will be employed in a weight ratio to the other therapeutic agent (depending upon its mode of operation) within the range from about 0.01:1 to about 500:1, preferably from about 0.5:1 to about 100:1.
  • compounds useful in inhibiting the enzyme HMG-CoA reductase which inhibitors are useful as hypocholesterolemic agents, dyslipidemic agents, hypolipidemic agents, hypotriglyceridemic agents, anti-Alzheimer's disease agents, and antiosteoporosis agents as well as other uses as described herein.
  • coronary events refers to myocardial infarction, myocardial revascularization procedures, angina, cardiovascular death and acute coronary syndrome.
  • cardiovascular diseases or events refers to atherosclerosis of the coronary arteries, myocardial infarction, including primary MI and secondary MI, recurrent myocardial infarction, angina pectoris (including stable and unstable angina), congestive heart failure, and sudden cardiac death.
  • Cerebrovascular diseases or events refers to cerebral infarction or stroke (caused by vessel blockage or hemmorage), or transient ischemia attack (TIA), syncope, atherosclerosis of the intracranial and/or extracranial arteries, and the like.
  • cholesterol-related diseases refers to diseases involving elevated levels of LDL cholesterol, diseases involving regulation of LDL receptors, diseases involving reduced levels of HDL cholesterol, dyslipidemia, hyperlipidemia, elevated LDL Pattern B, elevated LDL Pattern A, hypercholesterolemia, hypo ⁇ -lipoproteinemia (low HDL cholesterol syndrome), hyperlipoproteinemia, elevated Lp(a) levels, hypertriglyceridemia, other aberrations of apolipoprotein B metabolism, heterozygous familial, presumed familial combined and non-familial (non-FH) forms of primary hypercholesterolemia (including Frederickson Types IIa and IIb), cholesterol ester storage disease, and cholesterol ester transfer protein disease, and related diseases.
  • Dysmetabolic Syndrome includes hyperglycemia and/or prediabetic insulin resistance syndrome, and is characterized by an initial insulin resistant state generating hyperinsulinemia, dyslipidemia, and impaired glucose tolerance, which can progress to Type II diabetes, characterized by hyperglycemia, which can progress to diabetic complications.
  • diabetes complications include retinopathy, neuropathy and nephropathy, and other known complications of diabetes.
  • other type(s) of therapeutic agents refers to one or more antidiabetic agents (other than compounds of formula I), one or more anti-obesity agents, and/or one or more lipid-lowering agents, one or more lipid modulating agents (including anti-atherosclerosis agents), other types of anti-atherosclerosis agents, and/or one or more antiplatelet agents, one or more agents for treating hypertension, one or more anti-cancer drugs, one or more agents for treating arthritis, one or more anti-osteoporosis agents, one or more agents for treating immunomodulatory diseases, and/or one or more agents for treating anorexia nervosa.
  • lipid-modulating agent refers to agents which lower LDL and/or raise HDL and/or lower triglycerides and/or lower total cholesterol and/or other known mechanisms for therapeutically treating lipid disorders.
  • anti-atherosclerosis agents refers to conventional anti-atherosclerosis agents including lipoxygenase inhibitors, ACAT inhibitors, PPAR ⁇ agonists, dual PPAR ⁇ / ⁇ agonists, CETP inhibitors, antioxidants, PPAR ⁇ agonists, phospholipase inhibitors including PLA-2 inhibitors and/or other known anti-atherosclerotic agents.
  • salts refer to basic salts formed with inorganic and organic bases.
  • Such salts include ammonium salts; alkali metal salts, such as lithium, sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; salts with organic bases, such as amine like salts (e.g., dicyclohexylamine salt, benzathine, N-methyl-D-glucamine, and hydrabamine salts); and salts with amino acids like arginine, lysine and the like; and zwitterions, the so-called “inner salts”.
  • Nontoxic, pharmaceutically acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product.
  • Preferred are sodium and calcium salts.
  • salts also includes acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohalic acid such as HCl or HBr, with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, (for example aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as (C 1 -C 4 )
  • the compounds of structure I may form a pharmaceutically acceptable salt such as alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium as well as zinc or aluminum and other cations such as ammonium or choline, amino acid salts such as lysine (D or L), amine salts such as diethanolamine, ethylenediamine, t-butylamine, t-octylamine, tris-(hydroxymethyl)aminomethane (TRIS), N-methyl glucosamine (NMG), triethanolamine, dicyclohexylamine, methylamine and dehydroabietylamine.
  • alkali metal salts such as lithium, sodium or potassium
  • alkaline earth metal salts such as calcium or magnesium as well as zinc or aluminum and other cations such as ammonium or choline
  • amino acid salts such as lysine (D or L)
  • amine salts such as diethanolamine, ethylenediamine, t-buty
  • alkyl or “alk” as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons, containing 1 to 20 carbons, preferably 1 to 10 carbons, more preferably 1 to 8 carbons, in the normal chain, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethyl-pentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like.
  • Lower alkyl refers to such groups containing 1-6 carbon atoms. Unless specified otherwise, alkyl groups may be optionally substituted with 1 to 4 substituents.
  • the substituents include halo, for example F, Br, Cl or I or CF 3 , alkyl, alkoxy, aryl, aryloxy, aryl(aryl) or diaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, hydroxy, hydroxyalkyl, acyl, cycloheteroalkyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, nitro, cyano, thio
  • cycloalkyl as employed herein alone or as part of another group includes saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclic alkyl, bicyclic alkyl (or bicycloalkyl) and tricyclic alkyl, containing a total of 3 to 20 carbons forming the ring, preferably 3 to 10 carbons, forming the ring and which may be fused to 1 or 2 aromatic rings as described for aryl, which includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl, any of which groups may be optionally substituted with 1 to 4 substituents, which may be the same or different at each occurrence, such as halogen, alkyl, alkoxy, hydroxy,
  • cycloalkenyl as employed herein alone or as part of another group refers to cyclic hydrocarbons containing 3 to 12 carbons, preferably 5 to 10 carbons and 1 or 2 double bonds.
  • exemplary cycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, and cycloheptadienyl, which may be optionally substituted as defined for cycloalkyl.
  • alkanoyl or “alkylcarbonyl” as used herein alone or as part of another group refers to alkyl linked to a carbonyl group.
  • lower alkenyl or “alkenyl” as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 1 to 8 carbons in the normal chain, which include one to six double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkyn
  • lower alkynyl or “alkynyl” as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons and more preferably 2 to 8 carbons in the normal chain, which include one triple bond in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl,3-undecynyl, 4-dodecynyl and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl,
  • arylalkenyl and arylalkynyl as used alone or as part of another group refer to alkenyl and alkynyl groups as described above having an aryl substituent.
  • alkyl groups as defined above have single bonds for attachment to other groups at two different carbon atoms, they are termed “alkylene” groups and may optionally be substituted with 1 or 2 substituents as defined above for “alkyl”, such as, for example, alkyl, halo, hydroxy, alkoxy and/or cycloalkyl.
  • alkenyl groups as defined above and alkynyl groups as defined above, respectively, have single bonds for attachment at two different carbon atoms, they are termed “alkenylene groups” and “alkynylene groups”, respectively, and may optionally be substituted with 1 or 2 substituents as defined above for “alkenyl” and “alkynyl”.
  • halogen or “halo” as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine as well as CF 3 , with chlorine or fluorine being preferred.
  • metal ion refers to alkali metal ions such as sodium, potassium or lithium and alkaline earth metal ions such as magnesium and calcium, as well as zinc and aluminum.
  • aryl refers to monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl including 1-naphthyl and 2-naphthyl) and may optionally include one to three additional rings fused to a carbocyclic ring or a heterocyclic ring (such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings for example and may be optionally substituted through available carbon atoms with 1, 2, or 3 groups selected from hydrogen, halo, haloalkyl, alkyl, haloalkyl, alkoxy, halophenyl, benzoyloxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl, cyclohe
  • lower alkoxy as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to an oxygen atom.
  • substituted amino refers to amino substituted with one or two substituents, which may be the same or different, such as alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. These substituents may be further substituted with a carboxylic acid and/or any of the substituents for alkyl as set out above.
  • amino substituents may be taken together with the nitrogen atom to which they are attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-I-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl, 1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy.
  • lower alkylthio as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to a sulfur atom.
  • lower alkylamino as employed herein alone or as part of another group includes any of the above alkyl, aryl or arylalkyl groups linked to a nitrogen atom.
  • acyl refers to an organic radical linked to a carbonyl group; examples of acyl groups include any of the R 1 or R 4 groups attached to a carbonyl, such as alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl, cycloalkanoyl, cycloheteroalkanoyl and the like.
  • cycloheteroalkyl refers to a 5-, 6- or 7-membered saturated or partially unsaturated ring which includes 1 to 2 hetero atoms such as nitrogen, oxygen and/or sulfur, linked through a carbon atom or a heteroatom, where possible, optionally via the linker (CH 2 ) r (where r is 1, 2 or 3), such as and the like.
  • the above groups may include 1 to 4 substituents such as alkyl, halo, oxo and/or any of of the alkyl substituents set out herein.
  • any of the cycloheteroalkyl rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.
  • heteroaryl refers to a 5- or 6-membered aromatic ring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur,and such rings fused to an aryl, cycloalkyl, heteroaryl or cycloheteroalkyl ring (e.g. benzothiophenyl, indolyl), and includes possible N-oxides.
  • the heteroaryl group may optionally include 1 to 4 substituents such as any of the substituents set out above for alkyl. Examples of heteroaryl groups include the following: and the like.
  • cycloheteroalkylalkyl as used herein alone or as part of another gorup refers to cycloheteroalkyl groups as defined above linked through a C atom or heteroatom to a (CH2) r chain.
  • heteroarylalkyl or “heteroarylalkenyl” as used herein alone or as part of another group refers to a heteroaryl group as defined above linked through a C atom or heteroatom to a —(CH 2 ) r — chain, alkylene or alkenylene as defined above.
  • polyhaloalkyl refers to an “alkyl” group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as CF 3 CH 2 , CF 3 or CF 3 CF 2 CH 2 .
  • heterocyclo or “heterocyclyl” as used herein refers to heteroaryl and cycloheteroalkyl.
  • polyhaloalkoxy refers to an “alkoxy” or “alkyloxy” group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as CF 3 CH 2 O, CF 3 O or CF 3 CF 2 CH 2 O.
  • alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclo groups may be attached through one or more single bonds to one or more attachement atoms.
  • these groups may be attached by double bonds to attachement atoms, and these groups may be referred to as ‘alkylidene’, ‘alkenylidene’, ‘alkynylidene’, ‘cycloalkylidene’ or ‘heterocyclidene’ groups.
  • Examples include methylidene ( ⁇ CH2), ethylidene ( ⁇ CHCH3), ethenylidene ( ⁇ C ⁇ CH2), cyclohexylidene and 2-pyranylidene These groups may be substitued as described above for alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclo.
  • All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form.
  • the compounds of the present invention can have asymmetric centers at any of the carbon atoms including any one or the R substituents. Consequently, compounds of formula I can exist in enantiomeric or diastereomeric forms or in mixtures thereof.
  • the processes for preparation can utilize racemates, enantiomers or diastereomers as starting materials. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods for example, chromatographic or fractional crystallization.
  • the compounds of the present invention can have asymmetric centers at certain of the nitrogen atoms. Consequently, these isomers or mixtures thereof are part of the present invention.
  • the compounds of the present invention may also display other instances of chirality, such as atropoisomerism. Thus, these isomers or mixtures thereof are part of the invention.
  • prodrug esters as employed herein includes esters and carbonates formed by reacting one or more hydroxyls of compounds of formula I with alkyl, alkoxy, or aryl substituted acylating agents employing procedures known to those skilled in the art to generate acetates, pivalates, methylcarbonates, benzoates and the like.
  • prodrug esters which are known in the art for carboxylic and phosphorus acid esters such as methyl, ethyl, benzyl and the like are included herein.
  • prodrug esters examples include
  • R a can be H, alkyl (such as methyl or t-butyl), arylalkyl (such as benzyl) or aryl (such as phenyl);
  • R d is H, alkyl, halogen or alkoxy,
  • R e is alkyl, aryl, arylalkyl or alkoxyl, and
  • n 1 is 0, 1 or 2.
  • Compound 3 can be converted to the key intermediate olefin 4 by reaction with the previously known sulfone 5 (Brodfuehrer, Paul R. et al. PCT Int. Appl. (2002), WO 0298854) and an organic base such as lithium, sodium or potassium bistrimethylsilyl amide.
  • an organic base such as lithium, sodium or potassium bistrimethylsilyl amide.
  • Compounds of formula 6 can be converted to certain compounds of the formula I (R 4 ⁇ H, compound Ib) by treatment with an aqueous protic acid such as hydrochloric acid, sulfuric acid or p-toluenesulfonic acid to give Ia followed by saponification with an aqueous base such as sodium hydroxide to give Ib.
  • an aqueous protic acid such as hydrochloric acid, sulfuric acid or p-toluenesulfonic acid
  • an aqueous base such as sodium hydroxide
  • 6 can be converted to compounds of the formula I (R 4 is other than H, such as alkyl, alkylsulfonyl, alkanoyl, alkoxycarbonyl etc., compound Ic) by an initial treatment with a base such as lithium bis-trimethylsilylamide followed by treatment with R 4 Hal (7) such as the corresponding alkyl halides, sulfonyl halides/anhydrides, acyl halides/anhydrides and alkyl chloroformates and the like to afford 8. Removal of the acetonide group and saponification as described above affords compounds of the formula Ic.
  • Ic can be converted to the free acid Ic′ by treating the salt Ic with an acid, preferably a mineral acid, such as HCl or H 2 SO 4 .
  • compound 4 can be converted directly to compound 8 by treatment with a preassembled amine R 3 R 4 NH (compound 5b) and a base such as lithium bistrimethylsilylamide and the like in THF or DMF. Removal of the acetonide group and saponification as described above affords compounds of the formula Ic.
  • compounds 6 or 8 can be converted to the lactones Id or Ie, respectively, by reaction with an acid such as trifluroracetic acid in methylene chloride or chloroform which can be converted to the compounds of formula I (compounds Ic or Ic) by treatment with aqueous sodium hydroxide (Scheme 2).
  • an acid such as trifluroracetic acid in methylene chloride or chloroform which can be converted to the compounds of formula I (compounds Ic or Ic) by treatment with aqueous sodium hydroxide (Scheme 2).
  • Other intermediates containing R 5 groups as described for formula I may be prepared from intermediate 10 or its protected analogs using common transformations known in the art, for example, oxidation, alkylation, displacement, addition and the like.
  • the aminopyridine 11 may be converted to the fluoropyridine 12 by treatment with sodium nitrite and tetrafluoroboric acid in water.
  • Treatment of 12 with a heterocyclic amine R 3 NH 2 (compound 5a) in the presence of a base such as lithium, sodium or potassium bistrimethylsilylamide in THF or DMF affords 13.
  • Compound 13 can be converted to the alcohol 14 via reduction with a hydride reducing agent such as DIBAL.
  • Oxidation of the alcohol 14 to the aldehyde 15 may be accomplished by using NaOCl in the presence of catalytic amounts of KBr and TEMPO in EtOAc or methylene chloride or by using Dess-Martin's periodinane in methylene chloride.
  • Ig may be converted to the corresponding free acid by treating Ig with an acid such as HCl or H 2 SO 4 .
  • compound 12 can be converted to 13a which can be converted to compounds of formula Ih where R 4 is other than H via reduction, oxidation, olefination and deprotection.
  • Ig and Ih can also be prepared from compound 9 via selective hydrolysis of the sterically less hindered ethyl ester followed by decarboxylation of the resulting acid 9a using methods and reagents known in the art (e.g. heating with Cu powder/quinoline, U.S. Pat. No. 4,405,552, 20 Sep. 1983).
  • the resulting intermediate 9b can be used to synthesize compounds of formulae If, Ig or Ih (where R 5 ⁇ H) in a manner described for intermediate 11.
  • Certain compounds of formula I where X ⁇ CR 5 and R 5 is alkoxyalkyl can also be prepared from compound 9 as outlined in Scheme 3.
  • conversion of the amino group of 9 to a fluoro group can be achieved by using sodium nitrite and tetrafluoroboric acid to afford 9c.
  • Coupling of 9c with 5b can afford 9d which can be reduced using diborane to give the alcohol 9e.
  • Treatment of 9e with alkyl halides, alkyl triflates and the like under basic conditions (NaH, LiH and the like) in THF or DMF can afford 9f.
  • Compounds containing dihydroxy acid HMG-CoA binding domain side chains may be prepared in homochiral form, which is preferred, or may be prepared as racemic mixtures (3S*, 5R*) and may later be resolved to obtain the 3S, 5R isomer.
  • the compounds of the invention are inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase and thus are useful in inhibiting cholesterol biosynthesis and/or in lowering triglycerides, in a manner similar to atorvastatin, pravastatin, simvastatin, lovastatin, cerivastatin, rosuvastatin, fluvastatin, pitavastatin, and the like.
  • HMG-CoA 3-hydroxy-3-methyl-glutaryl coenzyme A
  • a further aspect of the present invention is a pharmaceutical composition containing at least one of the compounds of formula I of the present invention in association with a pharmaceutical vehicle or diluent.
  • the pharmaceutical composition can be formulated employing conventional solid or liquid vehicles of diluents and pharmaceutical additives of a type appropriate to the mode of desired administration.
  • the compounds can be administered by an oral route, for example, in the form of tablets, capsules, granules or powders, or they can be administered by a parenteral route in the form of injectable preparations.
  • Such dosage forms contain from 0.1 to 1500 mg of active compound per dosage, for use in the treatment.
  • the dose to be administered depends on the unitary dose, the symptoms, and the age and the body weight of the patient.
  • the compounds of the present invention can be administered in a similar manner as known compounds suggested for use in inhibiting cholesterol biosynthesis, such as pravastatin, lovastatin, simvastatin, rosuvastatin, atorvastatin, cerivastatin, fluvastatin, pitavastatin, and the like, in mammalian species such as humans, dogs, cats and the like.
  • the compounds of the invention may be administered in an amount from about 0.1 to 500 mg in a single dose or in the form of individual doses from 1 to 4 times per day, preferably 0.5 to 200 mg daily or in sustained release form.
  • HMG CoA reductase inhibitors of formula I may be employed in combination with all therapeutic agents which are useful in combination with HMG CoA reductase inhibitors.
  • the compounds of structure I may be used in combination with one or more hypolipidemic agents or lipid-lowering agents, or lipid agents, or lipid modulating agents, and/or one or more other types of therapeutic agents including antidiabetic agents, anti-obesity agents, antihypertensive agents, platelet aggregation inhibitors, anti-Alzheimer's agents, anti-dementia agents, anti-osteoporosis agents, and/or hormone replacement therapeutic agents, and/or other therapeutic agents, and/or other cardiovascular agents (including anti-anginal agents, anti-arrhythmic agents, anti-atherosclerosis agents, anti-inflammatory agents, anti-platelet agents, anti-heart failure agents), anti-cancer agents, anti-infective agents, hormone replacement agents, growth hormone secretagogues, selective androgen receptor modulators (SARMs), and/or other therapeutic agents which may be administered orally in the same dosage form or in a separate oral dosage form, or by injection.
  • therapeutic agents including antidiabetic agents, anti-
  • the hypolipidemic agent or lipid-lowering agent or other lipid agent or lipid modulating agent which may be optionally employed in combination with the compounds of formula I of the invention may include 1,2,3 or more MTP inhibitors, HMG CoA reductase inhibitors, squalene synthetase inhibitors, PPAR ⁇ agonists, PPAR dual ⁇ / ⁇ agonists, PPAR ⁇ agonists, fibric acid derivatives, ACAT inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors, ileal Na + /bile acid cotransporter inhibitors, upregulators of LDL receptor activity, cholesteryl ester transfer protein inhibitors, bile acid sequestrants, and/or nicotinic acid and derivatives thereof.
  • MTP inhibitors employed herein include MTP inhibitors disclosed in U.S. Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S. Pat. No. 5,712,279, U.S. Pat. No. 5,760,246, U.S. Pat. No. 5,827,875, U.S. Pat. No. 5,885,983 and U.S. Pat. No. 5,962,440. Preferred are each of the preferred MTP inhibitors disclosed in each of the above patents and applications.
  • MTP inhibitors to be employed in accordance with the present invention include preferred MTP inhibitors as set out in U.S. Pat. Nos. 5,739,135 and 5,712,279, and U.S. Pat. No. 5,760,246.
  • MTP inhibitor 9-[4-[4-[[2-(2,2,2-Trifluoroethoxy)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide
  • the squalene synthetase inhibitors suitable for use herein include, but are not limited to, ⁇ -phosphono-sulfonates disclosed in U.S. Pat. No. 5,712,396, those disclosed by Biller et al, J. Med. Chem., 1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid (phosphinyl-methyl)phosphonates as well as other known squalene synthetase inhibitors, for example, as disclosed in U.S. Pat. No. 4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K., Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2, 1-40 (1996).
  • squalene synthetase inhibitors suitable for use herein include the terpenoid pyrophosphates disclosed by P. Ortiz de Montellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyl diphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs as disclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293, phosphinylphosphonates reported by McClard, R. W. et al, J.A.C.S., 1987, 109, 5544 and cyclopropanes reported by Capson, T. L., PhD dissertation, June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp 16, 17, 40-43, 48-51, Summary.
  • hypolipidemic agents suitable for use herein include, but are not limited to, fibric acid derivatives, such as fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like, probucol, and related compounds as disclosed in U.S. Pat. No.
  • bile acid sequestrants such as cholestyramine, colestipol and DEAE-Sephadex (Secholex®, Policexide®) and cholestagel (Sankyo/Geltex), as well as lipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide (Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinic acid (ER niacin
  • the other hypolipidemic agent may be an ACAT inhibitor (which also has anti-atherosclerosis activity) such as disclosed in, Drugs of the Future 24, 9-15 (1999), (Avasimibe); “The ACAT inhibitor, Cl-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters”, Nicolosi et al, Atherosclerosis (Shannon, Irel). (1998), 137(1), 77-85; “The pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoB100-containing lipoprotein”, Ghiselli, Giancarlo, Cardiovasc. Drug Rev.
  • the hypolipidemic agent may be an upregulator of LDL receptor activity such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).
  • the hypolipidemic agent may be a cholesterol absorption inhibitor preferably Schering-Plough's SCH48461 (ezetimibe) as well as those disclosed in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998).
  • the other lipid agent or lipid-modulating agent may be a cholesteryl transfer protein inhibitor (CETP) such as Pfizer's CP-529,414 (torcetrapib) as well as those disclosed in WO/0038722 and in EP 818448 (Bayer) and EP 992496, and Pharmacia's SC-744 and SC-795 as well as CETi-1 and JTT-705.
  • CETP cholesteryl transfer protein inhibitor
  • the hypolipidemic agent may be an ileal Na + /bile acid cotransporter inhibitor such as disclosed in Drugs of the Future, 24, 425-430 (1999).
  • the ATP citrate lyase inhibitor which may be employed in the combination of the invention may include, for example, those disclosed in U.S. Pat. No. 5,447,954.
  • the other lipid agent also includes a phytoestrogen compound such as disclosed in WO 00/30665 including isolated soy bean protein, soy protein concentrate or soy flour as well as an isoflavone such as genistein, daidzein, glycitein or equol, or phytosterols, phytostanol or tocotrienol as disclosed in WO 2000/015201;
  • a phytoestrogen compound such as disclosed in WO 00/30665 including isolated soy bean protein, soy protein concentrate or soy flour as well as an isoflavone such as genistein, daidzein, glycitein or equol, or phytosterols, phytostanol or tocotrienol as disclosed in WO 2000/015201;
  • Preferred hypolipidemic agents are cholesterol absorption inhibitors such as ezetimibe, cholesterol ester transfer protein (CETP) inhibitors such as torcetrapib and JTT-705, dual PPAR ⁇ / ⁇ agonists such as muraglitazar and tesaglitazar, as well as niacin and/or cholestagel.
  • cholesterol absorption inhibitors such as ezetimibe, cholesterol ester transfer protein (CETP) inhibitors such as torcetrapib and JTT-705
  • dual PPAR ⁇ / ⁇ agonists such as muraglitazar and tesaglitazar
  • niacin and/or cholestagel niacin and/or cholestagel.
  • the compounds of formula I of the invention will be employed in a weight ratio to the hypolipidemic agent (where present), within the range from about 500:1 to about 1:500, preferably from about 100:1 to about 1:100.
  • the dose administered must be carefully adjusted according to age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result.
  • hypolipidemic agent or other lipid agent or lipid modulating agent will be as disclosed in the various patents and applications discussed above.
  • the MTP inhibitor for oral administration, a satisfactory result may be obtained employing the MTP inhibitor in an amount within the range of from about 0.01 mg to about 500 mg and preferably from about 0.1 mg to about 100 mg, one to four times daily.
  • a preferred oral dosage form such as tablets or capsules, will contain the MTP inhibitor in an amount of from about 1 to about 500 mg, preferably from about 2 to about 400 mg, and more preferably from about 5 to about 250 mg, one to four times daily.
  • the squalene synthetase inhibitor may be employed in dosages in an amount within the range of from about 10 mg to about 2000 mg and preferably from about 25 mg to about 200 mg.
  • a preferred oral dosage form such as tablets or capsules, will contain the HMG CoA reductase inhibitor in an amount from about 0.1 to about 200 mg, preferably from about 0.5 to about 80 mg, and more preferably from about 1 to about 40 mg.
  • the anti-atherosclerotic agent includes a lipoxygenase inhibitor including a 15-lipoxygenase (15-LO) inhibitor such as benzimidazole derivatives as disclosed in WO 97/12615, 15-LO inhibitors as disclosed in WO 97/12613, isothiazolones as disclosed in WO 96/38144, and 15-LO inhibitors as disclosed by Sendobry et al “Attenuation of diet-induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties,” Brit. J. Pharmacology (1997) 120, 1199-1206, and Cornicelli et al, “15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target for Vascular Disease”, Current Pharmaceutical Design, 1999, 5, 11-20.
  • 15-LO 15-lipoxygenase
  • 15-LO 15-lipoxygenase
  • benzimidazole derivatives as disclosed in WO 97/12615
  • the antidiabetic agent which may be optionally employed in combination with the HMG-CoA reductase inhibitor of formula I may be 1,2,3 or more antidiabetic agents or antihyperglycemic agents including insulin secretagogues or insulin sensitizers, which may include biguanides, sulfonyl ureas, glucosidase inhibitors, aldose reductase inhibitors, PPAR ⁇ agonists such as thiazolidinediones, PPAR ⁇ agonists (such as fibric acid derivatives), PPAR ⁇ antagonists or agonists, aP2 inhibitors, PPAR ⁇ / ⁇ dual agonists, dipeptidyl peptidase IV (DP4) inhibitors, SGLT2 inhibitors, glycogen phosphorylase inhibitors, and/or meglitinides, and/or glucagon-like peptide-1 (GLP-1), and/or a PTP-1B inhibitor (protein tyrosine phosphatas
  • the antidiabetic agent may be an oral antihyperglycemic agent preferably a biguanide such as metformin or phenformin or salts thereof, preferably metformin HCl.
  • the compounds of structure I will be employed in a weight ratio to biguanide within the range from about 0.001:1 to about 10:1, preferably from about 0.01:1 to about 5:1.
  • the antidiabetic agent may also preferably be a sulfonyl urea such as glyburide (also known as glibenclamide), glimepiride (disclosed in U.S. Pat. No. 4,379,785), glipizide, gliclazide or chlorpropamide, other known sulfonylureas or other antihyperglycemic agents which act on the ATP-dependent channel of the ⁇ -cells, with glyburide and glipizide being preferred, which may be administered in the same or in separate oral dosage forms.
  • glyburide also known as glibenclamide
  • glimepiride also known as glimepiride
  • glipizide also known as gliclazide
  • chlorpropamide other known sulfonylureas or other antihyperglycemic agents which act on the ATP-dependent channel of the ⁇ -cells
  • glyburide and glipizide being
  • the compounds of structure I will be employed in a weight ratio to the sulfonyl urea in the range from about 0.01:1 to about 100:1, preferably from about 0.02:1 to about 5:1.
  • the compounds of structure I will be employed in a weight ratio to the glucosidase inhibitor within the range from about 0.01:1 to about 100:1, preferably from about 0.05:1 to about 10:1.
  • the compounds of structure I may be employed in combination with a PPAR ⁇ agonist such as a thiazolidinedione oral anti-diabetic agent or other insulin sensitizers (which has an insulin sensitivity effect in NIDDM patients) such as troglitazone (Warner-Lambert's Rezulin®, disclosed in U.S. Pat. No. 4,572,912), rosiglitazone (SKB), pioglitazone (Takeda), Mitsubishi's MCC-555 (disclosed in U.S. Pat. No.
  • a PPAR ⁇ agonist such as a thiazolidinedione oral anti-diabetic agent or other insulin sensitizers (which has an insulin sensitivity effect in NIDDM patients) such as troglitazone (Warner-Lambert's Rezulin®, disclosed in U.S. Pat. No. 4,572,912), rosiglitazone (SKB), pioglitazone (Takeda
  • Glaxo-Welcome's GL-262570 englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&J), JTT-501 (JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344 (Dr. Reddy/NN), or YM-440 (Yamanouchi), preferably rosiglitazone and pioglitazone.
  • the compounds of structure I may also be employed in combination with a antihyperglycemic agent such as insulin or slow release insulin (BasulinTM), or with glucagon-like peptide-1 (GLP-1) or mimetic such as GLP-1(1-36) amide, GLP-1(7-36) amide, GLP-1(7-37) (as disclosed in U.S. Pat. No. 5,614,492 to Habener, the disclosure of which is incorporated herein by reference), as well as AC2993 (Amylin) and LY-315902 (Lilly), which may be administered via injection, intranasal, inhalation or by transdermal or buccal devices.
  • a antihyperglycemic agent such as insulin or slow release insulin (BasulinTM)
  • GLP-1(1-36) amide, GLP-1(7-36) amide, GLP-1(7-37) as disclosed in U.S. Pat. No. 5,614,492 to Habener, the disclosure of which is incorporated here
  • metformin the sulfonyl ureas, such as glyburide, glimepiride, glipyride, glipizide, chlorpropamide and gliclazide and the glucosidase inhibitors acarbose or miglitol or insulin (injectable, pulmonary, buccal, or oral) may be employed in formulations as described above and in amounts and dosing as indicated in the Physician's Desk Reference (PDR).
  • PDR Physician's Desk Reference
  • metformin or salt thereof may be employed in amounts within the range from about 500 to about 2000 mg per day which may be administered in single or divided doses one to four times daily.
  • the PPAR anti-diabetic agent may be employed in amounts within the range from about 0.01 to about 2000 mg/day which may be administered in single or divided doses one to four times per day.
  • insulin and other anti-diabetic agents as set out above may be employed in formulations, amounts and dosing as indicated by the Physician's Desk Reference.
  • GLP-1 peptides or mimetics may be administered in oral buccal formulations, by nasal administration or parenterally as described in U.S. Pat. Nos. 5,346,701 (TheraTech), 5,614,492 and 5,631,224 which are incorporated herein by reference.
  • the antidiabetic agent or other lipid agent may also be a PPAR modulator such as a PPAR ⁇ / ⁇ dual agonist such as tesaglitazar (Astra/Zeneca), muraglitazar (Bristol Myers-Squibb), MK-767 (Merck/Kyorin/Banyu), GW-409544 (Glaxo-Wellcome), KRP297 (Kyorin Merck) as well as those disclosed by Murakami et al, “A Novel Insulin Sensitizer Acts As a Coligand for Peroxisome Proliferation-Activated Receptor Alpha (PPAR alpha) and PPAR gamma.
  • a PPAR modulator such as a PPAR ⁇ / ⁇ dual agonist such as tesaglitazar (Astra/Zeneca), muraglitazar (Bristol Myers-Squibb), MK-767 (Merck/Kyorin/Banyu), GW
  • the antidiabetic agent may be an SGLT2 inhibitor such as disclosed in U.S. Pat. Nos. 6,414,126 and 6,515,117, employing dosages as set out therein. Preferred are the compounds designated as preferred in the above patents.
  • the antidiabetic agent may be a DPP4 inhibitor such as disclosed in U.S. Pat. No. 6,395,767, U.S. Pat. No. 6,573,287, U.S. Pat. No. 6,395,767 (BMS-477118 (preferred), BMS-471211 and BMS 538,305), WO99/38501, WO99/46272, WO99/67279 (PROBIODRUG), WO99/67278 (PROBIODRUG), WO99/61431 (PROBIODRUG), NVP-LAF-237, NVP-DPP728A (1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine) (Novartis) as disclosed by Hughes et al, Biochemistry, 38(36), 11597-11603, 1999, TSL-225 (tryptophyl-1,2,3,4-tetrahydr
  • the meglitinide which may optionally be employed in combination with the compound of formula I of the invention may be repaglinide or Starlix® (Novartis), nateglinide (Novartis) or KAD1229 (PF/Kissei), with repaglinide being preferred.
  • the antidiabetic compound may be a melanocortin receptor agonist such as a spiropiperidine as disclosed in WO 99/64002.
  • the other type of therapeutic agent which may be optionally employed with the HMG CoA reductase inhibitor of formula I may be 1, 2, 3 or more of an anti-obesity agent including a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin and/or dopamine modulator/mimic, norepinephrine (NE) modulator/mimic, an aP2 inhibitor, a thyroid receptor beta drug, a PTP-1B inhibitor, an anorectic agent, a PPAR modulator including PPAR ⁇ antagonists, PPAR ⁇ agonists, PPAR ⁇ antagonists, a CCKA agonist, a leptin inhibitor such as a leptin receptor activator, a neuropeptide Y antagonist, a melanocortin-4-receptor (MC4R) agonist, a CB-1 inverse agonist, a fatty acid oxidation upregulator or inducer (such as Famoxin® Gen
  • the beta 3 adrenergic agonist which may be optionally employed in combination with a compound of formula I may be AJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other known beta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615, 5,491,134, 5,776,983 and 5,488,064, with AJ9677, L750,355 and CP331648 being preferred.
  • neuropeptide Y antagonists which may be optionally employed in combination with a compound of formula I include those described in WO 0113917 (BMS) or in U.S. Pat. No. 6,218,408 (Synaptic) and in WO 0114376 (Banyu).
  • the lipase inhibitor which may be optionally employed in combination with a compound of formula I may be orlistat or ATL-962 (Alizyme), with orlistat being preferred.
  • the serotonin and dopoamine modulator/mimic and/or norepinephrine modulator/mimic which may be optionally employed in combination with a compound of formula I may be sibutramine.
  • the anorectic agent which may be optionally employed in combination with a compound of formula I may be topiramate, Axokine® (Regeneron) (anlogue of Ciliary Neurotrophic Factor) dexamphetamine, phentermine, phenylpropanolamine or mazindol, with dexamphetamine or topiramate being preferred.
  • the thyroid receptor beta compound which may be optionally employed in combination with a compound of formula I may be a thyroid receptor ligand as disclosed in WO97/21993 (U. Cal SF), WO99/00353 (KaroBlo), GB98/284425 (KaroBio), and U.S. Provisional Application No. 60/183,223 filed Feb. 17, 2000, with compounds of the KaroBio applications and the above U.S. provisional application being preferred.
  • ACC inhibitors examples include those described in WO 03/072197.
  • 5-HT2c agonists examples include compounds as disclosed in WO 00/77010.
  • CCKA agonists which may be employed herein include Glaxo-SmithKline's GI-181,771 and Sanofi's SR146,131.
  • anti-obesity agents described above may be employed in the same dosage form with the compound of formula I or in different dosage forms, in dosages and regimens as generally known in the art or in the PDR.
  • the antihypertensive agents which may be employed in combination with the HMG CoA reductase inhibitors of the invention include ACE inhibitors, angiotensin II receptor antagonists, MR agonist, NEP inhibitors such as candoxatril, NEP/ACE inhibitors, as well as calcium channel blockers (such as verapamil and amlodipine besylate), T-channel calcium antagonists (such as mibefradil), ⁇ -adrenergic blockers, diuretics, ⁇ -adrenergic blockers (such as doxazosin mesylate and terazosin HCl), dual action receptor antagonists (DARA), heart failure drugs such as digoxin, and other types of antihypertensive agents.
  • ACE inhibitors such as candoxatril, NEP/ACE inhibitors
  • calcium channel blockers such as verapamil and amlodipine besylate
  • T-channel calcium antagonists such as mibefradil
  • the angiotensin converting enzyme inhibitor which may be employed herein includes those containing a mercapto (—S—) moiety such as substituted proline derivatives, such as any of those disclosed in U.S. Pat. No. 4,046,889 to Ondetti et al mentioned above, with captopril, that is, 1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline, being preferred, and mercaptoacyl derivatives of substituted prolines such as any of those disclosed in U.S. Pat. No. 4,316,906 with zofenopril being preferred.
  • a mercapto (—S—) moiety such as substituted proline derivatives, such as any of those disclosed in U.S. Pat. No. 4,046,889 to Ondetti et al mentioned above, with captopril, that is, 1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline, being preferred, and mercaptoacyl
  • angiotensin converting enzyme inhibitors which may be employed herein include any of those disclosed in U.S. Pat. No. 4,374,829 mentioned above, with N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline, that is, enalapril, being preferred, any of the phosphonate substituted amino or imino acids or salts disclosed in U.S. Pat. No.
  • NEP/ACE inhibitors and dosages thereof which are designated as preferred in the above patents/applications which U.S. patents are incorporated herein by reference; most preferred are omapatrilat, gemopatrilat ([S [(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-acetic acid) and CGS 30440.
  • Dual action receptor antagonists suitable for use herein include those disclosed in U.S. applications Ser. No. 09/513,779, filed Feb. 25, 2000, and Ser. No. 09/604,322, filed Jun. 26, 2000.
  • Anti-thrombotic agents which may be employed in combination with compounds of formula I of the invention include melagatran and ximelagatran (ExantaTM Astra Zeneca), warfarin and Factor Xa inhibitors such as razaxaban.
  • Antiosteoporosis agents suitable for use herein in combination with the HMG CoA reductase inhibitors of the invention include parathyroid hormone or bisphosphonates, such as MK-217 (alendronate) (Fosamax®) as well as Ca receptor agonists and progestin receptor agonists. Dosages employed will be as set out in the PDR.
  • the hormone replacement therapeutic agents where present, will be employed in dosages as set out in the latest edition of the PDR.
  • examples of such agents include selective estrogen receptor modulators (SERMs) such as raloxifen, tamoxifen or lasoxifen.
  • SERMs selective estrogen receptor modulators
  • the HMG CoA reductase compound of the invention may also be employed in combination with a tyrosine kinase inhibitor such as disclosed in WO 2000/053605;
  • antineoplastic agent refers to compounds which prevent cancer cells from multiplying.
  • the antineoplastic agents used herein prevent cancer cells from multiplying by: (1) interfering with the cell's ability to replicate DNA, or (2) inducing apoptosis in the cancerous cells.
  • Particularly useful members of those classes not previously mentioned include, for example, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloro-methotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podophyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, and the like.
  • the pharmaceutical composition can be formulated employing conventional solid or liquid vehicles or diluents and pharmaceutical additives of a type appropriate to the mode of desired administration, such as pharmaceutically acceptable carriers, excipients, binders and the like.
  • the compounds can be administered to mammalian species including humans, monkeys, dogs, etc. by an oral route, for example, in the form of tablets, capsules, beads, granules or powders, or they can be administered by a parenteral route in the form of injectable preparations, or they can be administered intranasally or in transdermal patches.
  • Typical solid formulations will contain from about 0.1 to about 500 mg of a compound of formula I.
  • the dose for adults is preferably between 0.5 and 1,000 mg per day, which can be administered in a single dose or in the form of individual doses from 1-4 times per day and also single dose once weekly (5 to 1000 mg).
  • a typical injectable preparation is produced by aseptically placing 250 mg of compounds of structure I into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline, to produce an injectable preparation.
  • Lithium bis(trimethylsilyl)amide (1.0 M in THF, 407 mL, 0.47 mol) was added over 65 min to a stirred solution of 2-methyl-2H-[1,2,4]triazol-3-ylamine (37.5 g, 0.37 mol, prepared as described by Barascut, Jean L. et al., Bull. Soc. Chim. Fr. (1973), (5) part 2, 1849-53) and iodomethane (66.6 mL, 1.11 mol) in THF (1.2 L) under nitrogen at 0° C. After stirring at 0° C. for 1.5 h, additional lithium bis(trimethylsilyl)amide (1.0 M in THF, 90 mL, 0.09 mol) was added over 10 min.
  • step E To a solution of the title compound prepared in a manner similar to that described in step E (234 g, 402.7 mmol) in IL THF was added 1N HCL (403 mL). The reaction mixture was stirred at RT for 6 h, then added a solution of NaOH (32.5 g) in 150 mL water followed by the addition of 100 mL methanol. The reaction mixture was stirred for 1.5 h at RT, diluted with water (200 mL) and extracted with EtOAc (3 ⁇ 500 mL).
  • the Example 1 Part C compound may also be prepared as described below.
  • This compound was prepared from the step B compound in a manner similar to that described for the title compound of step B, Example 1.
  • This compound was prepared from the step D compound in a manner similar to that described for the step C compound of Example 1.
  • step C The compound from step C (100 mg) was oxidized as described for the synthesis of the title compound of Example 3, step F to give 75 mg of the title compound.
  • step B To a solution of the title compound from step B (1.9 g) in 50 mL tetrafluoroboric acid at ⁇ 10° C. was added 3.0 g sodium nitrite in small portions. The mixture was stirred at ⁇ 10° C. for 30 minutes, added slowly to a saturated sodium bicarbonate solution. The mixture was extracted with EtOAc, the organic phase was dried over sodium sulfate, concentrated and the residue was purified by flash chromatography (silica gel/methylene chloride) to give the title compound (1.55 g) as a white solid.
  • step F To a stirred solution of the title compound from step F (7.0 g) in methylene chloride (100 mL) was sequentially added di-tert-butyldicarbonate (12.5 g) and 4-dimethylaminopyridine (DMAP, 7.01 g). The mixture was stirred at RT for 5 h, concentrated and the residue was subjected to flash chromatography (silica gel/hexane-EtOAc 85:15) to give the title compound (7.0 g) as a brown solid.
  • DMAP 4-dimethylaminopyridine
  • This compound was prepared from the title compound of step G as described for the synthesis of the title compound of Example 1, step D.
  • the title compound was prepared from the title compound of step A as described for the synthesis of the title compound of Example 3 step E.
  • the title compound was prepared from the title compound of step B as described for the synthesis of the title compound of Example 3 step F.
  • the title compound was prepared from the title compound of step C as described for the synthesis of the title compound of Example 3 step H.
  • the title compound was prepared from the title compound of step A as described for the synthesis of the title compound of Example 3 step E.
  • the title compound was prepared from the title compound of step B as described for the synthesis of the title compound of Example 3 step F.
  • the title compound was prepared from the title compound of step C as described for the synthesis of the title compound of Example 3 step H.
  • the title compound was prepared from the title compound of step D as described for the synthesis of the title compound of Example 3 step I.
  • Analytical LC retention time 23.5 minutes (YMC ODS S5 6 mm ⁇ 150 mm column/methanol-water-phophoric acid 10:90:0.2 to 90:10:0.2 gradient over 30 minutes, 1.5 mL/min. flow rate); (M+H) + 575 (carboxylic acid).
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